The present invention relates to starch capsules. More precisely, the invention relates to coated starch capsules and the manufacture of such capsules.
In oral medical treatment, it is often justifiable to direct the release of a drug at the area of the intestines on a spot-specific basis. Many drugs do not tolerate well the acidic conditions of the stomach or they irritate the mucous membranes of the stomach (even to the effect of causing corrosion of a different degree in long-term use). The intention is to direct such drugs in a controlled way to the small intestine or the large intestine where they are absorbed and/or take effect locally in the most efficient way. Oral dosing of new drugs with peptide and protein structures is also used with the intention to release drugs on the spot-specific basis (pharmaceutical peptides are acid-labile and are not absorbed until the large intestine). It has been predicted that the use of pharmaceutical peptides and proteins will increase, which has aroused the interest of pharmaceutical industry, among others, in spot-specific pharmaceutical preparations.
Traditionally, spot-specific pharmaceutical preparations (so-called entero preparations) are prepared in multiple stages by a film coating technique in which solid nuclei containing drugsxe2x80x94granules, pellets or tabletsxe2x80x94are enveloped in a pH-sensitive polymeric capsule. The manufacture involves some multivariable processes that are difficult to control. According to present knowledge, entero preparations should rather be formulated into multiple-unit preparations, for example, into film-coated granules or pellets which are encased in a capsule coat. The migration of the small entero granules and pellets in the alimentary tract, which are released from the multiple-unit preparations, is not dependent on the food consumed or on the speed of emptying the stomach.
The transfer of drugs in the intestines should be possible all the way to the large intestine and, on the other hand, it should be possible to store them at room temperature. Several drugs on the market are sensitive to fluctuations in ambient conditions during storage (for example, humidity, light, oxygen, and temperature). During storage, the drug may decompose chemically (chemical impurities), leading to impaired quality and efficacy of the phrmaceutical product. During storage, the physical and pharmaceutical properties of the drug formulation can also deteriorate. As regards solid drug formulations, for example, the package rarely gives sufficient protection to a labile drug and drug formulation, but other manufacturing methods should be used to guarantee the quality of the pharmaceutical preparation.
The purpose of the present invention is to provide a certain type of protective capsule which can be used to protect drugs against ambient impact so that the quality and the efficacy of the drugs will not change before they reach their destination. The purpose of the protective capsule is to protect the drugs against physical and chemical decomposition so that the drugs keep at room temperature for rather long periods of time. Another purpose of the protective capsule is to give protection against the acidity of the stomach and bile acids as well as other conditions in the intestines so that the quality and the efficacy of the drugs keep in the intestines as long as is appropriate from the viewpoint of the medicine""s effect.
The present invention is based on the surprising observation that capsules can be formed from starch granules which give the drugs exactly the desired protection.
International patent publication WO 89/04842 describes the use of starch granules as a carrier for absorbed functional compositions. The starch granules are treated with alpha-amylase or glucoamylase. The publication suggests that starch granules be used as adjuvants for antiperspirants or as bulking agents for foods and drinks. It suggests that liquid substances be formulated, by using treated starch granules, into a powder, paste or cream formulation which is easier to pack or otherwise more practical. To strengthen the structure of hydrolyzed starch granules, the publication suggests treatment of the starch with cross-linking agents, such as sodium trimetaphosphate. If the substance to be absorbed into the starch granules has a lipid character, the starch matrix can, according to the publication, be treated with substances that render the pore surfaces more lipophilic. Such substances include, for example, synthetic polymers such as methylcellulose. The publication mentions that the substances to be absorbed can be, for example, salad oils, flavours, insect repellents, insecticides, herbicides, perfumes, moisturizers, soaps, waxes, body creams and lotions, vitamins and therapeutic drugs.
U.S. Pat. No. 5,670,490 describes porous aggregates formed of starch granules with the aid of binding agents, the empty space inside the aggregates being used to carry various functional substances. The substances are released from the aggregate under the influence of mechanical compression/decomposition, by disintegration of the binding agents or other substances, or by dissolution or diffusion from the porous surface. The diameter of the round aggregates was 15-150 xcexcm. Typically, the binding agent was a polymer. The patent suggests the use of aggregates in formulating orally dosed pharmaceutical compounds, among others, so that the formulation protects the active ingredients against the acidic and decomposing conditions of the stomach and that the active ingredients would not be released until the small intestine. The aggregates were prepared by suspending the starch granules in a suitable solution containing binding agents and by spray drying the suspension. According to the publication, the aggregates could be coated with a polymer after putting the functional compounds inside the aggregates. The binding agents could be biodegradable polymers, such as polysaccharides (gums originating from algae or plants, pectins, agar-agar, alginate, gelatine, dextrin, starch derivatives) and cellulose-bearing substances, such as carboxy-methyl cellulose, hydroxy-methyl cellulose, hydroxy-propyl cellulose, etc., proteins, particularly those which are not inherently present in starch granules, as well as polyesters. The polymers could also be non-biodegradable, synthetic or semi-synthetic, such as polyvinyl alcohol poly-N-vinyl-2-pyrrolidone or polymers or copolymers of acrylic or methacrylic acid or their amide derivatives, such as polyacrylamide. The coating substances could be the same or different polymers than the binding agents. The functional substances that could be absorbed into the aggregates could be the same substances as listed in application WO 89/04842.
U.S. Pat. No. 4,551,177 describes a compressible starch that can be used as a binder for tablets. Cold-water-insoluble granular starch was treated with acid, alkali or alpha-amylase, whereby altered, weakened granules were obtained which, when compressed, showed a good binding capacity.
Patent publication EP 0 539 910 A1 describes the treatment of starch granules with an amylase. The intention was to modify the viscosity of the starch granules. The publication suggests that the amylase-treated starch granules be used in instant liquid food, for example, or as mixed with non-treated starch granules, whereby blends of starch granules having various viscosity values can be obtained. According to the publication, the amylase-treated starch granules adsorb hydrophobic substances such as aromatic compounds. The publication states that glucoamylase-treated starch granules are able to adsorb oils.
The publication of Milosevic et al., Journal of Controlled Release 38 (1996) 75-84, describes the use of amylose films to protect pharmaceutical preparations. According to the publication, insoluble polymers, such as ethyl cellulose, were used to control the swelling and decomposition of the amylose and, thus, the releasing speed of the drug in conditions that simulated the conditions of the alimentary tract. According to the publication, the release of the drug from the preparation was due to the decomposition of the amylose component of the compound under the effect of bacterial enzymes and not because of mechanical decomposition of the coating.
Prior art publications, such as the publications WO 89/04842 and U.S. Pat. No. 5,670,490 referred to above, suggest that various functional substances be protected by using starch granules. In the formation of aggregates described in U.S. Pat. No. 5,670,490, various binding agents are used, for example, various polymers which can be detrimental when taken into the organs or during the manufacturing process. One disadvantage of the method disclosed in patent publication WO 89/04842 is that hydrolyzed starch granules can, indeed, absorb various substances inside their porous structures, but the substances can be released out of the starch granules and, on the other hand, the substances are not protected against the impact of the environment (light, pH, humidity, oxygen, temperature).
The purpose of the present invention is to eliminate the disadvantages of the prior art technology and to provide a whole new protective method for drugs and pharmaceutical peptides and proteins which advantageously employs natural polymers. By using the method, various substances, other than drugs as well, can be protected against the effects of the environment during storage or in human or animal intestines.
The method according to the invention utilizes the porous structure of starch granules, as a consequence of which the desired substances can be attached to the surface of the starch granules or the starch granules can be filled with these substances. The surface of a granule is coated with a thin layer of a biopolymer that is capable of film forming, such as cellulose, pectin, protein, preferably starch. The starch surface can be formulated from starch dissolved in hot water or from a component of the starch, an amylose, or by closing the pores on the surface of the starch granule by smaller starch granules of a suitable size. In the method according to the invention, aggregates are not formed from the starch granules but the granules remain essentially separate.
The porosity of the starch granules can further be improved by hydrolyzing to change the structure thereof so that the surface has holes and the inside is porous, cavitary, whereby the internal space of the granule forms a hollow, capsule-type space. The capsule-type space of the hydrolyzed starch granules can be filled with desired substances. The larger the molecule size of the drug or other substance, the more advantageous it is that the starch granule be hydrolyzed because compounds having large molecules can be better accommodated into the cavities of the hydrolyzed starch granules.
The present invention is based on the fact that non-hydrolyzed or hydrolyzed starch granules filled with the desired substances are coated with natural biopolymers, preferably with starch. The starch, one of its component, a linear amylose in particular, is capable of film forming. The starch can be modified by physical means (for example, by means of temperature) so that it becomes more stable and more resistant against the liquids of the stomach and the small intestine. The various techniques for coating starch granules include spraying with a starch/amylose solution or mixing the granules with a starch/amylose solution and allowing the starch to crystallize onto the surface of the granule. The starch/amylose solution can also be precipitated onto the surface of the granules by using ethanol. According to one embodiment of the invention, the pores on the surface of the granule can be closed with suitably small starch granules. Instead of the starch/amylose, the coating of starch granules can be carried out by employing other biopolymers, if their film forming properties and dissolving properties are as good as those of the amylose starch. Such biopolymers include, for example, cellulose, pectin or protein.
According to an advantageous embodiment of the invention, the starch granules are hydrolyzed by using enzymes. The starch is hydrolyzed with amylolytic enzymes, such as alpha-amylases, xcex2-amylases, and glucoamylases. The amorphic components of the granule are hydrolyzed and the crystalline areas remain. These crystalline components are fairly stable also in the human alimentary tract. After hydrolyzation, the starch granule can be filled with the desired substances, such as drugs, pharmaceutical peptides or proteins. The ability of the starch capsules to preserve various hydrophilic and hydrophobic substances can be used, for example, to improve the stability of volatile drugs and flavouring agents.
The starch capsules are preferably prepared from natural starch. Starches of various origins deviate as to their size and composition. These differences can be utilized in different applications.
One object of the invention is starch capsules, which comprise starch granules which have a porous structure and are coated with biopolymer. Before coating, the starch capsules can be filled with desired substances.
Another object of the invention is a method for manufacturing the starch capsules, comprising the following stages:
selecting starch granules of a suitable size in accordance with the purpose of use,
coating the selected starch granules with a biopolymer. Before coating, the starch capsules can be filled with desired substances.
The porosity of the starch granules is preferably increased by hydrolyzing the starch granule so that its structure becomes more cavitary. The cavitary structure of the granules can accommodate more substances which the granules are to protect.
With the aid of the invention, considerable advantages can be obtained. The starch granules according to the invention keep well at room temperature for several months. Starch capsules according to the invention, containing drugs, can be kept at room temperature for long periods of time. The quality and the efficacy of the drug improve when the drug is not exposed to the effect of fluctuations in humidity, temperature, oxygen or acidity in its environment.
The efficacy of pharmaceutical substances encased in the starch capsules according to the invention improves when the release of the drug takes place at the desired spot in the small or the large intestine. On the basis of the invention, the planning of the oral dosage of whole new pharmaceutical substances can be started.
The durability of various substances added to foodstuffs, such as flavouring agents and spices, encased in the starch capsules according to the invention, and the release thereof when eating is improved. For example, the taste of sweets such as chewing gum keeps longer when the release of the flavouring agents encased in the starch granule takes place in a controlled way.
The durability of various enzymes can also be improved by attaching them to the surface of the starch granules or into their porous internal spaces, and by preferably coating them with a biopolymer. Examples of such enzymes include industrial enzymes, such as those used by the wood-processing, the textile, and the food industry, the activity and the efficacy of which should not essentially be reduced during preservation, storage and/or processing. For example, it is advantageous to protect baking enzymes with the capsules according to the invention because baking enzymes should keep active until they are used in baking. It is also advantageous to use capsules according to the invention to protect the enzymes used in the same way as drugs, such as the enzyme that decomposes lactose, because they should withstand preservation and storage, as well as the intestinal conditions.